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Results for “FOLIC ACID ANTAGONISTS”

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At least 343 records · Page 19Linked to original sources
PubMed1985

Goldenhar syndrome, anterior encephalocele, and aqueductal stenosis following fetal primidone exposure.

Fetal exposure to primidone was associated with Goldenhar syndrome, hemifacial microsomia, tetralogy of Fallot, aqueductal stenosis, and anterior encephalocele in this male infant. No similar cases in anticonvulsant-exposed pregnancies were found on literature review, despite the increased incidence of other anomalies following such exposure. Goldenhar syndrome, especially related to rare central nervous system anomalies, is reviewed. Experimental production of hemifacial microsomia by a folic acid antagonist, triaxene, is mediated via hemorrhage in the fetus. Intraventricular hemorrhage was noted in this infant as were dilated lateral and third ventricles. The hemorrhagic diathesis and/or the folic acid depletion of newborns following fetal anticonvulsant exposure may have been the underlying mechanism.

Adult↗
PubMed1994

Folate deficiency and congenital malformations induced by pyrimethamine in the rat.

In order to establish a relationship between the appearance of congenital malformations and the decrease of folic acid in rat mothers and embryos, a folic acid antagonist, pyrimethamine (PY), was administered. On the 12th day of gestation/pregnant rats received an intraperitoneal injection of 12.5, 15.63, 18.75 or 25 mg/kg PY. On the 13th day of gestation folic acid was measured in different maternal and embryonic tissues obtained after surgical hysterectomy of 1 uterine horn. On the 21st day of gestation malformations were studied on live fetuses remaining in the opposite horn. The folate levels were identical in all maternal tissues. The concentration of folic acid significantly decreased (50%) within the embryonic tissues in all PY-treated groups. A decrease of fetal weight occurred in the 18.75 and 25 mg/kg PY groups. Malformations were observed in the same groups. A dysfunction of the placental transfer of folates is hypothesized.

Animals↗
PubMed2006

[Pharmacogenetics and pharmacogenomics].

Genetic polymorphisms can lead to drug adverse effects because certain allelic variants of genes that encode enzymes, targets or carriers involved in drug metabolism, are associated with an increase or a loss of function. Drug metabolism takes place essentially in the liver and is regulated by phase I enzymes (including several cytochrome P450 isoenzymes), the role of which is to make drug metabolites more polar by hydroxylation, and by phase II enzymes that catalyse conjugation reactions. Cytochromes P450 isoenzymes control 80% of oxidative reactions, owing to their low substrate specificity. The most extensively studied polymorphisms are those of CYP2D6 and CYP2C9, which are frequent and affect the metabolism of many drugs. For example, several CYP2C9 gene variants are associated with lower activity of the corresponding enzyme, potentially leading to drug overdose. Thiopurine methyl transferase and UDP-glucuronyl transferase are phase II enzymes that conjugate respectively 6-mercaptopurine metabolites with a methyl radical and metabolites of irinotecan (an anti-tumour drug) with a glucuronyl radical. Mutations in the corresponding genes can, through a loss of function, lead to excessively high levels of active metabolites, with a risk of bone marrow aplasia. The action of vitamin K antagonists is influenced by polymorphisms of vitamine K epoxyde reductase, the target molecule of vitamin K. A mutation in the methylene tetrahydrofolate reductase gene diminishes the folate pool and thereby increases the effects of methotrexate, a folic acid antagonist. Resistance to the anti-platelet effect of aspirin can be due to polymorphisms that affect other platelet aggregation pathways. Genotyping results must be confirmed by phenotyping, which examines the rate of transformation of a drug into its metabolites and shows whether the increase or decrease in this rate is linked to a specific polymorphism. Somatic mutations in malignant tumours can modify the response to anticancer drugs, and should therefore be taken into account. The National Academy of Medicine recommends:--development of genomic analyses for frequent polymorphisms in patients warranting treatment with drugs that have severe adverse effects;--collection of DNA samples from patients participating in drug trials in order to examine the possible relation between adverse effects and gene polymorphisms;--creation of biological resource centers in hospitals for the storage and analysis of tissue specimens.

Genotype↗
PubMed1976

Rapid radioimmunoassay for methotrexate in biological fluids.

We report a radioimmunoassay for the cytostatic folic acid antagonist methotrexate. Antiserum was raised in rabbits immunized with a conjugate of methotrexate and methylated bovine serum albumin. The calibration curve of the assay is linear from 1 to 100 ng methotrexate per 100-mul sample, 0.1 ng methotrexate still inhibiting the binding of the tracer by 20%. The coefficient of variation ranged from 4.04% to 11.58%. The reaction of the antiserum proved to be specific for methotrexate, as only insignificant interference could be demonstrated with folic acid, folinic acid (leucovorin), or tetrahydrofolic acid. With the method, results are available about 20 h after blood sampling at a daily capacity of at least 48 samples (i.e., about 15 determinations), depending on the equipment. Concentrations of methotrexate in plasma and erythrocytes were determined in five patients who were on continuous treatment with the drug. In one patient the concentration/time curves were followed in plasma and erythrocytes by frequent determinations for 24 h after a parenteral dose. The results indicate that the procedure is well suited for clinical investigations.

Adult↗
PubMed1956

Current trends in cancer chemotherapy.

Current trends in the search for chemical compounds having an inhibitory action on the growth of malignant cells are reviewed in this article. Several agents are sufficiently promising that clinical trials with them are in progress. One of these, an aromatic nitrogen mustard (C.B. 1348), appears to be useful as an adjunctive therapeutic measure in patients with malignant lymphoma, chronic lymphocytic leukemia, and mycosis fungoides who have become refractory to other methods of treatment. The introduction of certain purine antagonists, of which 6-mercaptopurine has been given the most extensive clinical trial, has opened up a new field of experimental and clinical investigation. 6-mercaptopurine and related compounds appear to be particularly useful in the treatment of acute leukemia in adults, but they are also useful, together with the folic acid antagonists and the steroid hormones, in the management of acute leukemia in children. While at present chemotherapeutic agents currently under investigation rarely cause significant regression of inoperable primary or metastatic solid tumors, the possibility of eventual more effective control in many types of malignant disease is not as dismal as it was a decade ago.

Adult↗
PubMed1984

Responses of solitary retinal horizontal cells to L-glutamate and kainic acid are antagonized by D-aspartate.

Solitary horizontal cells dissociated from goldfish retinas depolarized when exposed to micromolar doses of either L-glutamate or kainic acid. The responses to both of these agonists were antagonized by D-aspartate, and unaffected by L-aspartate, L-glutamic acid diethyl ester and folic acid. the results of the present study thus suggest that L-glutamate and kainic acid may produce depolarizations of horizontal cells by interacting with pharmacologically similar membrane receptors.

Animals↗
PubMed2006

Evaluation of clinically relevant glutamate pathway inhibitors in in vitro model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, inherited and fatal neurodegenerative disorder for which there is, at present, no effective treatment or cure. Striatal medium spiny neurons (MSN) are the most sensitive in HD. Dysregulation of glutamate/calcium signaling pathway emerges as a possible cause of striatal MSN neurodegeneration in HD. Here we evaluated five clinically relevant glutamate pathway inhibitors using previously developed in vitro HD model. We found that folic acid, gabapentin and lamotrigine did not protect HD neurons from glutamate-induced cell death, but memantine and riluzole were protective. Our results provide further support to potential use of memantine and riluzole for treatment of HD.

Amines↗
PubMed1997

Prospectively measured red cell folate levels in methotrexate treated patients with rheumatoid arthritis: relation to withdrawal and side effects.

OBJECTIVE: To investigate whether red cell folate (RCF) levels relate to side effects, withdrawals, or disease activity during treatment with the folic acid antagonist methotrexate (MTX) for rheumatoid arthritis (RA). METHODS: Side effects were recorded monthly, RCF levels were measured by lactoglobulin binding radioassays, and 8 variables for disease activity were measured in a placebo controlled double blind trial of 28 weeks' duration comparing efficacy of MTX (n = 23) and D-penicillamine (n = 23). RESULTS: From Week 20 RCF levels decreased only in the MTX group (p < 0.02), and 5 MTX treated patients withdrew due to side effects. Withdrawals had lower RCF values at Weeks 0 and 9 compared to the remaining patients (p < 0.05). Folate deficiency evolved in 5 patients; 2 of these developed cytopenia. Aberrations in the scheduled dosage increase were related to lower pretreatment values of RCF (p = 0.007). Side effect scores were inversely correlated to RCF values at Weeks 0, 9, and 28 (p < 0.05). RCF levels measured concomitantly with liver enzyme elevation were lower than the remaining values (p < 0.001). When side effects were reported, 96% of concomitantly measured RCF values were below 800 nmol/l. RCF values at entry did not correlate to improvement in any variable for disease activity, or a graded overall improvement. CONCLUSION: RCF levels decrease during MTX treatment and relate to side effects, withdrawals, liver enzyme elevations and aberrant MTX dosage increase, but not to the therapeutic effect. RCF above 800 nmol/l protects against side effects.

Aged↗
PubMed1981

Enzymatic synthesis and function of folylpolyglutamates.

Derivatives of folic acid occur in nature predominantly as poly (gamma-glutamyl) derivatives containing 2-8 glutamate residues. The data regarding the function of these derivatives, and their biosynthesis by eucaryotic and procaryotic folylpolyglutamate synthetases, is reviewed. The most universal functions of folylpolyglutamates appear to be (a) as the actual cofactors in vivo for folate dependent enzymes, (b) as inhibitors of folate dependent enzymes for which they are not substrates, and (c) to increase retention of folates after they are transported into cells as monoglutamates. Folylpolyglutamates also have numerous specialized functions in specific organisms, e.g. as structural components of some coliphage, and as allosteric regulators in Neurospora crassa. A single enzyme appears responsible for synthesis of all polyglutamate derivatives, regardless of length. With the recent introduction of sensitive assays this folylpolyglutamate synthetase has begun to be characterized. Although procaryotic and eucaryotic synthetases have many dissimilar properties, both types catalyze the ATP-dependent addition of L-glutamate to the gamma-carboxyl of the glutamate present in the folate. Both types also require a monovalent cation and relatively high pH. The most significant differences between the two types are in their folate substrate specificity and the product lengths derived from various folates.

Animals↗
PubMed1998

Adult and two children with fetal methotrexate syndrome.

The folic acid antagonists, methotrexate and aminopterin, are known to be teratogenic in humans. The critical period for their teratogenecity is suspected to be between 6 to 8 weeks post-conception. Fetal exposure from 10 to 32 weeks weeks post-conception to methotrexate alone or in combination with other anti-cancer drugs has not resulted in obvious teratogenic effects. Methotrexate is often used to treat cancers but is occasionally used as an abortifacient. The long-term outcome of the fetal aminopterin syndrome has been published in only four adults. We report on a 28-year-old man with fetal methotrexate syndrome and two children with mild manifestations of the syndrome. One child was inadvertently exposed to methotrexate from 7 1/2 through 30 weeks post-conception because his mother was receiving it for treatment of breast cancer. The other was exposed from 11 weeks and 5 days through 25 weeks in an attempt to induce abortion. The 28-year-old man has craniofacial and digital anomalies, growth retardation but normal intelligence as noted in the previously reported cases. These cases remind us of the teratogenicity of methotrexate and should serve as a warning that if methotrexate is used as an abortifaciant and an abortion does not ensue, there is a teratogenic risk.

Abnormalities, Drug-Induced↗
PubMed2003

Methotrexate/misoprostol embryopathy: report of four cases resulting from failed medical abortion.

Methotrexate, a methyl derivative of aminopterin, is a folic acid antagonist and a known human teratogen; misoprostol is a synthetic prostaglandin E1 analog that causes uterine contractions. Recently, there has been resurgence in the use of methotrexate in combination with misoprostol or of methotrexate alone for the treatment of unwanted or ectopic pregnancies, respectively. This report documents the findings in four infants who were exposed prenatally to methotrexate alone or in combination with misoprostol in a failed attempt at medical abortion or treatment of ectopic pregnancy. All patients demonstrated growth deficiency, with growth parameters <10th centile, and all displayed features consistent with methotrexate and/or misoprostol embryopathy. Since an increasing number of medical abortions are being performed, it is important for physicians to recognize the associated teratogenic effects of these abortifacients. Data from the patients herein described should prompt obstetricians and other health care practitioners who prescribe these medications to counsel their patients regarding these risks, especially if the treatment regimen fails to induce an abortion.

Abnormalities, Multiple↗
PubMedDate not supplied

Methotrexate in rheumatoid arthritis: an update.

Methotrexate, a folic acid antagonist, is being employed more frequently in an attempt to control rheumatoid arthritis that has not responded adequately to conventional therapies. Systemic administration of 7.5-15 mg weekly in a pulse fashion appears to be effective without precipitating serious adverse effects. Concern over potentially serious adverse effects and lack of well-controlled clinical trials have limited its use to severe, refractory disease. Its use in the future is likely to increase in these patients because of its ease of administration and the high response rate noted in clinical studies.

Arthritis, Rheumatoid↗